US4361564A - Renoprotective treatments employing vasodilator compounds - Google Patents
Renoprotective treatments employing vasodilator compounds Download PDFInfo
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- US4361564A US4361564A US06/232,650 US23265081A US4361564A US 4361564 A US4361564 A US 4361564A US 23265081 A US23265081 A US 23265081A US 4361564 A US4361564 A US 4361564A
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- failure
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- vasodilator
- hydrochloride
- renal damage
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- 229940124549 vasodilator Drugs 0.000 title claims abstract description 26
- 239000003071 vasodilator agent Substances 0.000 title claims abstract description 26
- 238000011282 treatment Methods 0.000 title claims abstract description 15
- 230000001084 renoprotective effect Effects 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 title 1
- 239000000126 substance Substances 0.000 claims abstract description 13
- 238000000034 method Methods 0.000 claims abstract description 11
- LCPDWSOZIOUXRV-UHFFFAOYSA-N phenoxyacetic acid Chemical class OC(=O)COC1=CC=CC=C1 LCPDWSOZIOUXRV-UHFFFAOYSA-N 0.000 claims abstract description 5
- ZUXNZUWOTSUBMN-UHFFFAOYSA-N hydralazine hydrochloride Chemical compound Cl.C1=CC=C2C(NN)=NN=CC2=C1 ZUXNZUWOTSUBMN-UHFFFAOYSA-N 0.000 claims description 17
- 229960005384 hydralazine hydrochloride Drugs 0.000 claims description 16
- 230000001315 anti-hyperlipaemic effect Effects 0.000 claims description 13
- ZNIFSRGNXRYGHF-UHFFFAOYSA-N Clonidine hydrochloride Chemical compound Cl.ClC1=CC=CC(Cl)=C1NC1=NCCN1 ZNIFSRGNXRYGHF-UHFFFAOYSA-N 0.000 claims description 7
- WFXFYZULCQKPIP-UHFFFAOYSA-N prazosin hydrochloride Chemical compound [H+].[Cl-].N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 WFXFYZULCQKPIP-UHFFFAOYSA-N 0.000 claims description 7
- 229960002925 clonidine hydrochloride Drugs 0.000 claims description 6
- 150000002632 lipids Chemical class 0.000 claims description 6
- 229960002386 prazosin hydrochloride Drugs 0.000 claims description 6
- 230000001242 postsynaptic effect Effects 0.000 claims description 3
- 102000004305 alpha Adrenergic Receptors Human genes 0.000 claims description 2
- 108090000861 alpha Adrenergic Receptors Proteins 0.000 claims description 2
- 230000000903 blocking effect Effects 0.000 claims description 2
- 102000015007 alpha-adrenergic receptor activity proteins Human genes 0.000 claims 1
- 108040006816 alpha-adrenergic receptor activity proteins Proteins 0.000 claims 1
- 230000027455 binding Effects 0.000 claims 1
- 208000001647 Renal Insufficiency Diseases 0.000 abstract description 19
- 201000006370 kidney failure Diseases 0.000 abstract description 19
- 206010020772 Hypertension Diseases 0.000 abstract description 17
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 abstract description 12
- 208000031226 Hyperlipidaemia Diseases 0.000 abstract description 2
- 241000700159 Rattus Species 0.000 description 14
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 12
- 229950000958 halofenate Drugs 0.000 description 10
- BJBCSGQLZQGGIQ-UHFFFAOYSA-N 2-acetamidoethyl 2-(4-chlorophenyl)-2-[3-(trifluoromethyl)phenoxy]acetate Chemical compound C=1C=C(Cl)C=CC=1C(C(=O)OCCNC(=O)C)OC1=CC=CC(C(F)(F)F)=C1 BJBCSGQLZQGGIQ-UHFFFAOYSA-N 0.000 description 9
- 230000001631 hypertensive effect Effects 0.000 description 8
- 238000011321 prophylaxis Methods 0.000 description 8
- 230000009467 reduction Effects 0.000 description 8
- RYSMHWILUNYBFW-UHFFFAOYSA-N 4-amino-2-[6-(dimethylamino)purin-9-yl]-5-(hydroxymethyl)oxolan-3-ol Chemical compound C1=NC=2C(N(C)C)=NC=NC=2N1C1OC(CO)C(N)C1O RYSMHWILUNYBFW-UHFFFAOYSA-N 0.000 description 7
- 235000005911 diet Nutrition 0.000 description 7
- 230000037213 diet Effects 0.000 description 7
- 229960002474 hydralazine Drugs 0.000 description 6
- 201000005206 focal segmental glomerulosclerosis Diseases 0.000 description 5
- DDRJAANPRJIHGJ-UHFFFAOYSA-N creatinine Chemical compound CN1CC(=O)NC1=N DDRJAANPRJIHGJ-UHFFFAOYSA-N 0.000 description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
- 241000282414 Homo sapiens Species 0.000 description 3
- 239000005018 casein Substances 0.000 description 3
- 208000029078 coronary artery disease Diseases 0.000 description 3
- 206010061989 glomerulosclerosis Diseases 0.000 description 3
- 208000017169 kidney disease Diseases 0.000 description 3
- 230000003907 kidney function Effects 0.000 description 3
- 230000017074 necrotic cell death Effects 0.000 description 3
- 230000001681 protective effect Effects 0.000 description 3
- 206010008111 Cerebral haemorrhage Diseases 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 239000003524 antilipemic agent Substances 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 208000020832 chronic kidney disease Diseases 0.000 description 2
- 229940109239 creatinine Drugs 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 201000001474 proteinuria Diseases 0.000 description 2
- 238000011699 spontaneously hypertensive rat Methods 0.000 description 2
- 230000008719 thickening Effects 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- GJSURZIOUXUGAL-UHFFFAOYSA-N Clonidine Chemical compound ClC1=CC=CC(Cl)=C1NC1=NCCN1 GJSURZIOUXUGAL-UHFFFAOYSA-N 0.000 description 1
- 206010029164 Nephrotic syndrome Diseases 0.000 description 1
- 101100386054 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) CYS3 gene Proteins 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 230000000326 anti-hypercholesterolaemic effect Effects 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 208000022831 chronic renal failure syndrome Diseases 0.000 description 1
- 235000019504 cigarettes Nutrition 0.000 description 1
- KNHUKKLJHYUCFP-UHFFFAOYSA-N clofibrate Chemical compound CCOC(=O)C(C)(C)OC1=CC=C(Cl)C=C1 KNHUKKLJHYUCFP-UHFFFAOYSA-N 0.000 description 1
- 229960001214 clofibrate Drugs 0.000 description 1
- 229960002896 clonidine Drugs 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000034994 death Effects 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 239000003651 drinking water Substances 0.000 description 1
- 235000020188 drinking water Nutrition 0.000 description 1
- 238000002651 drug therapy Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000024924 glomerular filtration Effects 0.000 description 1
- 230000000055 hyoplipidemic effect Effects 0.000 description 1
- 208000006575 hypertriglyceridemia Diseases 0.000 description 1
- 150000002462 imidazolines Chemical class 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 238000012335 pathological evaluation Methods 0.000 description 1
- IENZQIKPVFGBNW-UHFFFAOYSA-N prazosin Chemical compound N=1C(N)=C2C=C(OC)C(OC)=CC2=NC=1N(CC1)CCN1C(=O)C1=CC=CO1 IENZQIKPVFGBNW-UHFFFAOYSA-N 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 150000003246 quinazolines Chemical class 0.000 description 1
- 231100001028 renal lesion Toxicity 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 101150035983 str1 gene Proteins 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 230000035488 systolic blood pressure Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
Definitions
- the present invention relates generally to the treatment of renal conditions and more particularly to the prevention of renal failure through the administration of substances which have antihyperlipidemic characteristics.
- Severe hypertension itself was considered as a high risk factor not only to coronary artery disease but in addition to renal diseases and cerebral hemorrhage.
- Treatment of severe hypertension with vasodilators has been effective in reducing the hypertensive condition which has resulted in a concomitant reduction in renal failure and cerebral hemorrhages in such patients.
- hypertensive rats were fed an antihyperlipidemic substance comprising a phenoxyacetic acid derivative (halofenate). These rats exhibited a reduced tendency to renal failure when injected with puromycin aminonucleoside.
- an antihyperlipidemic substance comprising a phenoxyacetic acid derivative (halofenate).
- vasodilator hydralazine not only provided antihypertensive results but also functioned as an antihyperlipidemic agent reducing the triglyceride and cholesterol levels.
- the reduction in cholesterol levels were more pronounced than the reduction in triglyceride levels.
- vasodilators which are helpful in reducing hypertensive conditions also provide beneficial reduction in lipid levels thus reducing a risk factor in renal failure.
- Vasodilators could be administered as a protective or prophylactic treatment at the onset of the hyperlipidemic condition so as to prevent renal failure.
- Another object of the present invention is to provide a new medical use for a vasodilator.
- a further object of the present invention is to provide a method of reducing the risk of incurring renal failure by prophylactic treatment with a combination of substances including at least one vasodilator and one antihyperlipidemic agent.
- a still further object of the present invention is to provide a method of reducing the risk of incurring renal damage by prophylactic treatment with at least one alpha-adrenergic receptor binding agent.
- the invention finds embodiment in certain combinations of elements and arrangements of parts by which the said objects and certain other objects are hereinafter attained.
- At least one antihyperlipidemic substance comprising a vasodilator to hosts as a protective or prophylactic treatment against renal failure.
- a preferred substance comprising hydralazine hydrochloride may be given in quantities of between 40 and 200 milligrams per day to human hosts.
- hydralazine hydrochloride With respect to hydralazine hydrochloride, this vasodilator has been prescribed as a hypotensive agent in dosages of up to 400 mg. per day.
- Hydralazine hydrochloride is also referred to as 1-Hydrazinophthalazine Hydrochloride which shown by the following formula: ##STR1##
- prazosin hydrochloride is a quinazoline derivative.
- Prazosin hydrochloride comprises the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-2(2-furoyl) piperazine and its structural formula is: ##STR2## It has been employed in the treatment of hypertension in humans with a daily dosage of between 1 milligram and 40 milligrams. The dosage in patients with chronic renal failure will be reduced in proportion to the reduction in renal function.
- Clonidine hydrochloride which comprises an imidazoline derivative.
- Clonidine hydrochloride is also referred to as 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. It has been administered to adult humans for treatment of hypertension in dosages of 0.1 milligrams through 2.4 milligrams per day.
- clonidine hydrochloride With respect to clonidine hydrochloride, it is believed that its mechanism of action appears to be the stimulation of central postsynaptic alpha-receptors, while prazosin hydrochloride and hydralazine hydrochloride are believed to function by blocking postsynaptic alpha-adrenoceptors.
- vasodilators which provide antihyperlipidemic effects are well suited for the treatment of renal conditions as a prophylaxis against renal failure pursuant to the present invention.
- SHR is a spontaneously hypertensive rat
- SLC sucrose (60% or 45%)-lard (5% or 20%)-casein (21%)-cellulose (10%) rat food;
- Hal is halofenate (0.05% of sucrose-lard diet) as a supplement
- 1An is 1 I.P.I. of puromycin aminonucleoside (90 mg/kg);
- LC is lab chow (fed to SHR controls);
- PTG and PTC are plasma triglycerides and total cholesterol in mg/dl;
- SBP is systolic blood pressure in mm HG
- BW% is body weight as percent of initial weight
- 2KW is the weight of two kidneys in grams
- UPr is proteinuria/creatinine, mg/mg
- BUN is blood urea-N, mg/dl
- SGS is segmental glomerulosclerosis
- GGS is global glomerulosclerosis
- FGS is total focal glomerulosclerosis
- Thg is arteriolar thickening
- Nec is arteriolar necrosis.
- hydralazine hydrochloride was effective in reducing the plasma total cholesterol (PTC) levels which were elevated by SLC diet and by chronic renal damage induced by puromycin aminonucleoside and was effective in reducing elevated plasma triglyceride levels induced by the sucrose-lard-casein diets (SLC).
- PTC plasma total cholesterol
- SLC sucrose-lard-casein diets
- the tabulated pathological evaluation indicated a marked reduction in renal damage by hydralazine therapy and even a more marked reduction by combined treatment of halofenate and hydralazine.
- Severe renal lesions including renal arteriolar necrosis (Nec) were observed only in hypertensive rats fed the sucrose-lard-casein diet and which received the puromycin aminonucleoside.
- the severity of the lesions including focal glomerulosclerosis, segmental glomerulosclerosis and global glomerulosclerosis was significantly reduced in the hydralazine, the halofenate and the combined hydralazine-halofenate treated rats along with a reduction in arteriolar thickening and necrosis.
- vasodilators such as prazosine hydrochloride and clonidine hydrochloride may have a tendency to reduce serum cholesterol levels in severely hypertensive hosts as indicated in the following article: Kirkendall, Walter M. et al "Prazosine and Clonidine for Moderately Severe Hypertension", J.A.M.A. Dec. 1, 1978, Volume 240, No. 23, pp. 2553-6.
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
A treatment method and substances have been found to reduce the risk of incurring renal damage or failure. Vasodilators useful for the treatment of hypertension have been found to lower cholesterol levels and prevent renal failure or damage. These substances are administered alone or in combination with other substances useful in the treatment of hyperlipidemia such as phenoxyacetic acid derivatives.
Description
This application is a continuation in part of an application entitled IMPROVEMENTS IN PREVENTING RENAL FAILURE, Ser. No. 965,059, filed Nov. 30, 1978 and issued Feb. 10, 1981 as U.S. Pat. No. 4,250,191. The prior copending application was directed to a method of preventing renal failure by administering an antihyperlipidemic substance comprising a phenoxyacetic acid derivative.
1. Field of the Invention
The present invention relates generally to the treatment of renal conditions and more particularly to the prevention of renal failure through the administration of substances which have antihyperlipidemic characteristics.
2. Brief Description of the Prior Art
In the past, elevated serum cholesterol and triglyceride concentrations were considered as high risk factors together with cigarette smoking and hypertension for coronary artery disease. This was especially so when both lipid parameters were elevated simultaneously. Therefore it was not surprising to find the exaggerated incidence of atherosclerosis and coronary heart disease in human nephrotic syndrome, the advanced stages of which were traditionally accompanied by high lipid levels.
As a countermeasure to coronary and vascular problems, it was suggested that antihyperlipidemic drugs be used. Indeed, recent studies indicate that the drug clofibrate gave significant protection against ischemic heart disease and death in patients with angina pectoris. Studies with patients who have undergone renal transplantation have also revealed that renal failure was usually accompanied by hypertriglyceridaemia. This condition was generally believed to be a secondary condition or complication of an existing renal damage.
Severe hypertension itself was considered as a high risk factor not only to coronary artery disease but in addition to renal diseases and cerebral hemorrhage. Treatment of severe hypertension with vasodilators has been effective in reducing the hypertensive condition which has resulted in a concomitant reduction in renal failure and cerebral hemorrhages in such patients.
As set forth in the copending related application Ser. No. 965,059, issued Feb. 10, 1981 as U.S. Pat. No. 4,250,191 and incorporated herein by reference, substances useful in the treatment of hyperlipidemia such as phenoxyacetic acid derivatives have been found to reduce or prevent renal failure. It occurred to the inventor that the relationship between increased lipid levels and renal disease might serve to increase or aggravate renal disease associated with hypertension.
An experiment was proposed to feed a number of spontaneously hypertensive rats a diet which would encourage a hyperlipidemic condition. In some of these rats chronic renal disease was induced by injection of puromycin aminonucleoside. The hyperlipidemic rats experienced marked renal failure. Comparative tests with controls (hypertensive rats fed hypolipidemic diets) did not show this renal failure.
Some of the hypertensive rats were fed an antihyperlipidemic substance comprising a phenoxyacetic acid derivative (halofenate). These rats exhibited a reduced tendency to renal failure when injected with puromycin aminonucleoside.
Further rats were fed a vasodilator (hydralazine). These rats also exhibited a reduced tendency to renal failure when injected with puromycin aminonucleoside. Additional rats that were fed a combination of halofenate and hydralazine also indicated a reduced tendency to renal failure.
The vasodilator hydralazine not only provided antihypertensive results but also functioned as an antihyperlipidemic agent reducing the triglyceride and cholesterol levels. The reduction in cholesterol levels were more pronounced than the reduction in triglyceride levels.
It was concluded that vasodilators which are helpful in reducing hypertensive conditions also provide beneficial reduction in lipid levels thus reducing a risk factor in renal failure. Vasodilators could be administered as a protective or prophylactic treatment at the onset of the hyperlipidemic condition so as to prevent renal failure.
It is an object of the present invention to provide a method of reducing the risk of incurring the renal damage by prophylactic treatment with a vasodilator.
Another object of the present invention is to provide a new medical use for a vasodilator.
It is a further object of the present invention to administer a substance used in the treatment of hypertensive conditions as a prophylaxis against renal failure per se.
A further object of the present invention is to provide a method of reducing the risk of incurring renal failure by prophylactic treatment with a combination of substances including at least one vasodilator and one antihyperlipidemic agent.
A still further object of the present invention is to provide a method of reducing the risk of incurring renal damage by prophylactic treatment with at least one alpha-adrenergic receptor binding agent.
Other objects in part will be obvious and in part will be pointed out hereinafter.
With these ends in view, the invention finds embodiment in certain combinations of elements and arrangements of parts by which the said objects and certain other objects are hereinafter attained.
In accordance with the invention, it is proposed to administer at least one antihyperlipidemic substance comprising a vasodilator to hosts as a protective or prophylactic treatment against renal failure. A preferred substance comprising hydralazine hydrochloride may be given in quantities of between 40 and 200 milligrams per day to human hosts.
With respect to hydralazine hydrochloride, this vasodilator has been prescribed as a hypotensive agent in dosages of up to 400 mg. per day. Hydralazine hydrochloride is also referred to as 1-Hydrazinophthalazine Hydrochloride which shown by the following formula: ##STR1##
A further preferred vasodilator, prazosin hydrochloride is a quinazoline derivative. Prazosin hydrochloride comprises the hydrochloride salt of 1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-2(2-furoyl) piperazine and its structural formula is: ##STR2## It has been employed in the treatment of hypertension in humans with a daily dosage of between 1 milligram and 40 milligrams. The dosage in patients with chronic renal failure will be reduced in proportion to the reduction in renal function.
A further well known vasodilator is clonidine hydrochloride which comprises an imidazoline derivative. Clonidine hydrochloride is also referred to as 2-(2,6-dichlorophenylamino)-2-imidazoline hydrochloride. It has been administered to adult humans for treatment of hypertension in dosages of 0.1 milligrams through 2.4 milligrams per day.
With respect to clonidine hydrochloride, it is believed that its mechanism of action appears to be the stimulation of central postsynaptic alpha-receptors, while prazosin hydrochloride and hydralazine hydrochloride are believed to function by blocking postsynaptic alpha-adrenoceptors.
Other vasodilators which provide antihyperlipidemic effects are well suited for the treatment of renal conditions as a prophylaxis against renal failure pursuant to the present invention.
The use of hydralazine hydrochloride as a prophylaxis against renal failure was demonstrated to be statistically significant *(P less than 0.05) in the following tabulated test conducted over the course of one year with spontaneously hypertensive white female rats. The one year test was the equivalent to half of a lifespan of the rats and to approximately 30-35 years in man.
__________________________________________________________________________
Av. Glmlscl (GS) Arteriolar GFR
(n)
PTG
PTC
SBP
BW %
2KW
SGS
+ GGS
= FGS
Thg
Nec
UPr
BUN
%
__________________________________________________________________________
SLC/SHR (5)
493
99 138
131 1.58
0.2 0.1 0.3
0.3
0 9 26 94
SLC/SHR + Hal (8)
158'
63'
132
117'
1.48
0 0 0 0.1
0 9 20 122
SLC/SHR + Hdz (6)
209'
84 80'
130 1.35
0 0 0 0 0 7 21 115
SLC/SHR + Hdz + Hal
(8)
218'
50'
81'
118'
1.41
0 0 0 0 0 11 29 82
SLC/SHR + 1An (8)
387
215'
166
119 2.59'
1.7' 2.7' 4.4'
2.8'
1.1
85'
97'
25'
SLC/SHR + 1An + Hal
(8)
263*
98*
134*
117 1.81*
1.2 0.8* 2.0*
0.9*
0* 44*
28*
85*
SLC/SHR + 1An + Hdz
(7)
350
117*
96*
130 1.86*
1.1 0.6* 1.7*
0.6*
0* 31*
26*
92*
SLC/SHR + 1An + Hdz + Hal
(8)
247*
82*
89*
119 1.67*
0.8* 0.6* 1.4*
0.4*
0* 38*
35 69
LC/SHR (2)
150
78 150
126 1.49
0.5 0 0.5
0 0 6 22 112
LC/SHR + Hdz (1)
121
74 105
122 1.50
0 0 0 0.5
0 9 22 109
LC/SHR + 1An (2)
256
124
132
127 1.83
2.0 1.0 3.0
0.5
0 50 25 96
LC/SHR + 1An + Hdz
(2)
140
83 125
132 1.73
0 0.2 0.2
0 0 32 22 109
__________________________________________________________________________
' significant difference from SLC/SHR (P less than 0.05)
*significant difference from SLC/SHR + 1An
SHR is a spontaneously hypertensive rat;
SLC is sucrose (60% or 45%)-lard (5% or 20%)-casein (21%)-cellulose (10%) rat food;
Hal is halofenate (0.05% of sucrose-lard diet) as a supplement;
Hdz is hydralazine hydrochloride, 80 mg. per liter of drinking water (4-6 mg/kg. per day ingested by the rats);
1An is 1 I.P.I. of puromycin aminonucleoside (90 mg/kg);
LC is lab chow (fed to SHR controls);
PTG and PTC are plasma triglycerides and total cholesterol in mg/dl;
SBP is systolic blood pressure in mm HG;
BW% is body weight as percent of initial weight;
2KW is the weight of two kidneys in grams;
UPr is proteinuria/creatinine, mg/mg;
BUN is blood urea-N, mg/dl;
GFR is glomerular filtration rate (% normal=2400/BUN).
The tabulated results of the example also indicate the renohistopathology evaluation by semiquantitation over a range of 0-4+'s and the following were noted.
SGS is segmental glomerulosclerosis;
GGS is global glomerulosclerosis;
FGS is total focal glomerulosclerosis;
Thg is arteriolar thickening; and
Nec is arteriolar necrosis.
The above study established that hydralazine hydrochloride was effective in reducing the plasma total cholesterol (PTC) levels which were elevated by SLC diet and by chronic renal damage induced by puromycin aminonucleoside and was effective in reducing elevated plasma triglyceride levels induced by the sucrose-lard-casein diets (SLC). The study thus established that in addition to its known antihypertensive activity, the vasodilator hydralazine hydrochloride has significant antihyperlipidemic including antihypercholesterolemic activity.
The tabulated pathological evaluation indicated a marked reduction in renal damage by hydralazine therapy and even a more marked reduction by combined treatment of halofenate and hydralazine. Severe renal lesions including renal arteriolar necrosis (Nec) were observed only in hypertensive rats fed the sucrose-lard-casein diet and which received the puromycin aminonucleoside. The severity of the lesions including focal glomerulosclerosis, segmental glomerulosclerosis and global glomerulosclerosis was significantly reduced in the hydralazine, the halofenate and the combined hydralazine-halofenate treated rats along with a reduction in arteriolar thickening and necrosis.
The measured renal functions during the study clearly established the renoprotective efficacy of hydralazine hydrochloride, as well as halofenate. For example, proteinuria/creatinine (UPr) which was induced by the puromycin aminonucleoside and enhanced by the SLC diet was significantly diminished by hydralazine hydrochloride and by halofenate. An analysis of the tabulated BUN values confirmed the renal protective action of the hydralazine hydrochloride and halofenate. It was noted, however, that no additional renal function protection occurred with combined drug therapy when compared with the significant functional renoprotective activity of hydralazine hydrochloride or halofenate.
It was concluded that the antihyperlipidemic action of other vasodilators would provide similar beneficial results. It has been suggested that other vasodilators such as prazosine hydrochloride and clonidine hydrochloride may have a tendency to reduce serum cholesterol levels in severely hypertensive hosts as indicated in the following article: Kirkendall, Walter M. et al "Prazosine and Clonidine for Moderately Severe Hypertension", J.A.M.A. Dec. 1, 1978, Volume 240, No. 23, pp. 2553-6.
The observed renoprotective activity of the vasodilator hydralazine hydrochloride apparently results from its antihyperlipidemic characteristics. It is believed that all vasodilators which exhibit antihyperlipidemic characteristics are useful as prophylactic substances against renal damage and/or failure, particularly in hosts who are not subject to severe hypertension.
Thus, it will be seen that there is provided renoprotective treatments which achieve the various objects of the invention and which are well suited to meet the conditions of practical employment.
As various possible embodiments might be made of the present invention and since various changes might be made in the exemplary embodiments described herein, it is to be understood that all matter herein described or exemplified is to be interpreted as illustrative rather than in a limiting sense.
Claims (6)
1. A method of treating renal damage or failure in a host in need of treatment comprising administering to said host an effective amount for treating renal damage or failure; a vasodilator having postsynaptic alpha-adrenoceptor blocking activity and having antihyperlipidemic characteristics which lower the lipid levels in the bloodstream of the host, the vasodilator being selected from a group consisting of hydralazine hydrochloride and prazosin hydrochloride.
2. A method of treating renal damage or failure in accordance with claim 1 wherein the vasodilator is hydralazine hydrochloride and the hydralazine hydrochloride is administered to the host in substantially daily quantities totalling approximately from 40 milligrams through 200 milligrams.
3. A method of treating renal damage or failure in accordance with claim 1 wherein the vasodilator is prazosin hydrochloride and the prazosin hydrochloride is administered to the host in substantially daily quantities totalling approximately from 1 milligram through 40 milligrams.
4. A method of treating renal damage or failure in accordance with claim 1 wherein the clonidine hydrochloride is administered to the host in substantially daily quantities totalling approximately from 0.1 milligram through 2.4 milligrams.
5. A method of treating renal damage or failure in accordance with claim 1 including administering to the host an effective amount for treating renal damage or failure of a further substance having antihyperlipidemic characteristics comprising a phenoxyacetic acid derivative.
6. A method of treating renal damage or failure in a host in need of treatment comprising administering to said host an effective amount for treating renal damage or failure a vasodilator having central alpha-adrenergic receptor binding activity and having antihyperlipidemic characteristics which lower the lipid levels in the bloodstream of the host, said vasodilator is clonidine hydrochloride.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/232,650 US4361564A (en) | 1978-11-30 | 1981-02-09 | Renoprotective treatments employing vasodilator compounds |
| US06/424,076 US4532135A (en) | 1981-02-09 | 1982-09-27 | Renoprotective treatments employing vasodilator compounds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US05/965,059 US4250191A (en) | 1978-11-30 | 1978-11-30 | Preventing renal failure |
| US06/232,650 US4361564A (en) | 1978-11-30 | 1981-02-09 | Renoprotective treatments employing vasodilator compounds |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US05/965,059 Continuation-In-Part US4250191A (en) | 1978-11-30 | 1978-11-30 | Preventing renal failure |
Related Child Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/424,076 Continuation-In-Part US4532135A (en) | 1981-02-09 | 1982-09-27 | Renoprotective treatments employing vasodilator compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US4361564A true US4361564A (en) | 1982-11-30 |
Family
ID=26926202
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US06/232,650 Expired - Fee Related US4361564A (en) | 1978-11-30 | 1981-02-09 | Renoprotective treatments employing vasodilator compounds |
Country Status (1)
| Country | Link |
|---|---|
| US (1) | US4361564A (en) |
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4758569A (en) * | 1987-08-26 | 1988-07-19 | Pfizer Inc. | Doxazosin as an anti-atherosclerosis agent |
| US4868179A (en) * | 1987-04-22 | 1989-09-19 | Cohn Jay N | Method of reducing mortality associated with congestive heart failure using hydralazine and isosorbide dinitrate |
| US5703212A (en) * | 1994-04-19 | 1997-12-30 | Kanebo, Ltd. | Preventive for circulatory diseases |
| US6514941B1 (en) | 1999-12-10 | 2003-02-04 | Campina Melkunie B.V. | Method of preparing a casein hydrolysate enriched in anti-hypertensive peptides |
| US20030087878A1 (en) * | 2001-10-31 | 2003-05-08 | Jakob Vinten-Johansen | Methods and formulations for minimizing spasticity in blood vessel grafts |
| US20060014829A1 (en) * | 2004-07-16 | 2006-01-19 | Nitromed, Inc. | Methods for reducing hospitalizations related to heart failure |
| US20080293724A1 (en) * | 2006-02-17 | 2008-11-27 | Nitromed, Inc. | Methods Using Hydralazine Compounds and Isosorbide Dinitrate or Isosorbide Mononitrate |
| US20090306081A1 (en) * | 2006-05-16 | 2009-12-10 | Letts L Gordon | Solid Dosage Formulations of Hydralazine Compounds and Nitric Oxide Donor Compounds |
-
1981
- 1981-02-09 US US06/232,650 patent/US4361564A/en not_active Expired - Fee Related
Non-Patent Citations (5)
| Title |
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| Brogden et al., Drugs 14, pp. 163-197, (1977). * |
| Kirkendall et al., JAMA, vol. 240, No. 23, pp. 2553-2556, 12/1/78. * |
| O'Connor et al., J. of Cardiovascular Pharmacology, vol. 1, No. 6, (1979), (Supplement), pp. 538-542. * |
| The Merck Index, 9th Ed., (1976), pp. 307, 625 & 998. * |
| The Merck Index, 9th Ed., (1979), p. 599. * |
Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4868179A (en) * | 1987-04-22 | 1989-09-19 | Cohn Jay N | Method of reducing mortality associated with congestive heart failure using hydralazine and isosorbide dinitrate |
| US4758569A (en) * | 1987-08-26 | 1988-07-19 | Pfizer Inc. | Doxazosin as an anti-atherosclerosis agent |
| US5703212A (en) * | 1994-04-19 | 1997-12-30 | Kanebo, Ltd. | Preventive for circulatory diseases |
| US6514941B1 (en) | 1999-12-10 | 2003-02-04 | Campina Melkunie B.V. | Method of preparing a casein hydrolysate enriched in anti-hypertensive peptides |
| US20050118562A1 (en) * | 2001-10-31 | 2005-06-02 | Emory University | Methods for minimizing spasticity in blood vessel grafts |
| US6900008B2 (en) | 2001-10-31 | 2005-05-31 | Emory University | Methods and formulations for minimizing spasticity in blood vessel grafts |
| US20030087878A1 (en) * | 2001-10-31 | 2003-05-08 | Jakob Vinten-Johansen | Methods and formulations for minimizing spasticity in blood vessel grafts |
| US20060014829A1 (en) * | 2004-07-16 | 2006-01-19 | Nitromed, Inc. | Methods for reducing hospitalizations related to heart failure |
| US20060014828A1 (en) * | 2004-07-16 | 2006-01-19 | Nitromed, Inc. | Compositions and methods related to heart failure |
| US20090118293A1 (en) * | 2004-07-16 | 2009-05-07 | Nitromed, Inc. | Methods for reducing hospitalizations related to heart failure |
| US20090118294A1 (en) * | 2004-07-16 | 2009-05-07 | Manuel Worcel | Compositions and methods related to heart failure |
| US20080293724A1 (en) * | 2006-02-17 | 2008-11-27 | Nitromed, Inc. | Methods Using Hydralazine Compounds and Isosorbide Dinitrate or Isosorbide Mononitrate |
| US20090306081A1 (en) * | 2006-05-16 | 2009-12-10 | Letts L Gordon | Solid Dosage Formulations of Hydralazine Compounds and Nitric Oxide Donor Compounds |
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